The present invention relates generally to novel methods for the synthesis of benzoxazinone compounds which are useful as human immunodeficiency virus (HIV) reverse transcriptase inhibitors.
Reverse transcription is a common feature of retrovirus replication. Viral replication requires a virally encoded reverse transcriptase to generate DNA copies of viral sequences by reverse transcription of the viral RNA genome. Reverse transcriptase, therefore, is a clinically relevant target for the chemotherapy of retroviral infections because the inhibition of virally encoded reverse transcriptase would interrupt viral replication.
A number of compounds are effective in the treatment the human immunodeficiency virus (HIV) which is the retrovirus that causes progressive destruction of the human immune system with the resultant onset of AIDS. Effective treatment through inhibition of HIV reverse transcriptase is known for both nucleoside based inhibitors, such as azidothymidine, and non-nucleoside based inhibitors. Benzoxazinones have been found to be useful non-nucleoside based inhibitors of HIV reverse transcriptase. The benzoxazinone of the formula (VI-a): 
is not only a highly potent reverse transcriptase inhibitor, it is also efficacious against HIV reverse transcriptase resistance. Due to the importance of benzoxazinones as reverse transcriptase inhibitors, synthetic processes for their production need to be developed. 
Thompson et al, Tetrahedron Letters 1995, 36, 937-940, describe the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition followed by cyclization with a condensing agent to form the benzoxazinone shown above.
European Patent Application 582,455 A1 describes the synthesis of benzoxazinones via a three step process. 
This general method teaches (1) metallation of the pivalamide of parachloroaniline with n-butyllithium followed by nucleophilic substitution with an ester to form a ketone, (2) synthesis of a tertiary carbinol by Grignard addition to the ketone, and (3) cyclization of the unprotected amine with the carbinol by addition of a condensing agent to form a benzoxazinone.
Young et al, PCT International Patent Application Number WO 9520389 A1 describe benzoxazinones useful in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS. Application WO 9520389 A1 discloses methods of synthesis which are commensurate with EP 582,455 A1 above. Additionally, Young et al, Antimicrobial Agents and Chemotherapy 1995, 39, 2602-2605, in discussing the clinical benefit, the in vitro activity, and the pharmacokinetic activity of benzoxazinone (VI-a) in the treatment of HIV as an HIV reverse transcriptase inhibitor disclose an abbreviated synthesis of benzoxazinone (VI-a) commensurate with EP 582,455 A1 above wherein the tertiary carbinol is synthesized by addition of a cyclopropyl-ethynyl-lithium reagent before cyclizing the unprotected amine with the carbinol by addition of a condensing agent.
Muchowski and Venuti, J. Org. Chem. 1980, 45, 4798-4801, describe the ortho functionalization of N-(tert-butoxycarbonyl)aniline by a corresponding dilithio species using only tert-butyllithium as a practical means of synthesis of ortho-substituted anilines. This reference teaches away from the use of sec-butyllithium and n-butyllithium. The following references describe procedures for ortho lithiation on N-Boc-4-chloro-anilines using tert-butyllithium: Reed et al, Tetrahedron Letters 1988, 29, 5725-8; Cho et al, J. Org. Chem. 1991, 56, 7288-91; Berger et al, Heterocycles 1993, 36, 2051-8; Iwao, Heterocycles 1994, 38, 45-50; and Reuter et al, Tetrahedron Lett. 1994, 35, 4899-902.
Karlsson et al, Tetrahedron Letters 1989, 30, 2653-6, describe a cyclization process for synthesizing five membered cyclic carbamates from an aliphatic N-2-Boc-amino alcohol resulting in a monocyclic oxazolidone.
The formation of benzoxazinones by intramolecular nucleophilic alkoxide ion attack on ethyl and p-nitrophenyl carbamates has been described in the literature for the study of intramolecular enzyme-catalyzed reactions (see Hutchins and Fife, J. Am. Chem. Soc. 1973, 95, 3786-90). The rates of ring closure and phenoxide ion release from the ethyl and p-nitrophenyl esters of 2-hydroxymethyl-N-methylcarbanilic acid and 2-hydroxymethylcarbanilic acid were measured in water at 25xc2x0 under conditions which required excess potassium hydroxide concentrations.
Doller et al, PCT International Application Number WO 93/14054 describes a process for the production of substituted trifluoromethyl ketones of formula (XIV) 
by oxidation of the corresponding substituted trifluoromethyl alcohols.
The above methods for the syntheses of benzoxazinones use toxic, difficult to handle reagents and relatively expensive materials. Thus, it is desirable to discover new synthetic routes to benzoxazinones on a large scale which avoid toxic, difficult to handle reagents and provide high yields of desired benzoxazinones.
Accordingly, the present invention provides an improved synthetic process for the preparation of benzoxazinones. The process of the present invention eliminates use of highly toxic condensing agents such as phosgene and provides for a more efficient intramolecular cyclization using a stoichiometric equivalent of strong base. The present invention eliminates the use of highly toxic ceric ammonium nitrate or replaces messy HCl/EtOH/LiOH for the removal of camphanic acid with a considerably cleaner DMSO/H2O reaction.
The present invention provides novel processes for the addition of cyclopropylethynyl radical to N-Boc-aniline via the cyclopropylethynyl lithium or cyclopropylethynyl trifluoromethyl ketone to produce the carbinol necessary for the intramolecular cyclization reaction.
The present invention provides for intermediates as stable solids purifiable by recrystallization. None of the above-cited references describe the methods of the present invention for the synthesis of benzoxazinones useful as inhibitors of HIV reverse transcriptase.
The present invention concerns processes for the preparation of benzoxazinone compounds which are useful as HIV reverse transcriptase inhibitors. The processes of the present invention provide high yields, can be conducted on a kilogram scale, and yield stable intermediates. The invention further provides for a facile intramolecular cyclization under mild condition to form benzoxazinone compounds.
There is provided by this invention a process for the preparation of compounds of formula (VI) and derivatives thereof: 
wherein X, R2, and R3 are as defined below, said process comprising one or more of the following:
(1) (substitution) reacting a compound of formula (I): 
xe2x80x83wherein R1 is an amine protecting group, which forms a carbamate with the amine,
xe2x80x83with sec-butyllithium or another suitable lithiating agent, and ethyl trifluoroacetate in a suitable aprotic solvent, to form a compound of formula (II): 
(2) (addition) reacting a compound of formula (II) with cyclopropylethynyl lithium, which has been generated in situ by the reaction of 5-chloro-1-pentyne with n-butyllithium, in a suitable aprotic solvent, to form a compound of formula (III): 
(3) (cyclization) contacting a compound of formula (III) with n-butyllithium or a suitable strong base, to form a compound of formula (IV) 
(4) (chiral resolution) reacting a compound of formula (IV) with sodium hydride and camphanic acid chloride or a suitable chiral amine protecting group and separating the diastereomers to form a compound of formula (V): 
xe2x80x83wherein R4 is a chiral amine protecting group, and
(5) (nitrogen deprotection) contacting a compound of formula (V) with dimethylsulfoxide and water to form a compound of formula (VI).
In a first embodiment, the present invention provides a novel process for the preparation of compounds of formula (IV) and derivatives thereof: 
wherein:
X is halogen,
R2 is trihalomethyl or pentahaloethyl,
R3 is cyclopropylethynyl; said process comprising one or more of the following:
step (1) (nucleophilic substitution)
(a) contacting a compound of formula (I): 
xe2x80x83wherein R1 is an amine protecting group, which forms a carbamate with the amine,
xe2x80x83with a suitable lithiating agent in a suitable solvent, and
(b) contacting the resulting compound with an ester of the formula of R2COOR5, wherein xe2x80x94OR5 is a leaving group, to form a compound of formula (II): 
step (2) (addition)
(a) contacting 5-halo-1-pentyne with about two equivalents of a suitable metallating agent in a suitable solvent at a temperature sufficient to generate cyclopropylethynyl-M, wherein M is lithium or magnesium halide, in situ; and
(b) contacting the cyclopropylethynyl-M with a compound of formula (II) in a suitable solvent at a temperature sufficient to form a compound of formula (III): 
step (3) (cyclization) contacting a compound of formula (III) with a suitable strong base in a suitable aprotic solvent and heating to a temperature sufficient to form a compound of formula (IV).
In a preferred embodiment:
X is chloro;
R1 is selected from the group consisting of:
ethoxycarbonyl,
diisopropylmethoxycarbonyl,
tert-butyloxycarbonyl,
menthoxycarbonyl
bornyloxycarbonyl
benzyloxycarbonyl,
cyclopentyloxycarbonyl, and
adamantyloxycarbonyl;
R2 is trihalomethyl;
R3 is cyclopropylethynyl;
R5 is ethyl;
the suitable lithiating agent is selected from the group consisting of n-butyllithium, sec-butyllithium, and t-butyllithium;
the suitable metallating agent is selected from the group consisting of n-butyllithium, sec-butyllithium, and t-butyllithium; and
the suitable strong base is selected from the group consisting of potassium hexamethyldisilazide, sodium hydride, potassium hydride, lithium hydride, n-butyllithium, sec-butyllithium, t-butyllithium, phenyllithium, triphenylmethyllithium, and potassium t-butoxide.
In a more preferred embodiment, the compound of formula (IV) is a compound of formula (IV-a): 
said process comprises:
step (1) (substitution)
(a) contacting a compound of formula (I-a): 
with about two and one-half equivalents of sec-butyllithium in a suitable aprotic solvent at a temperature of between about xe2x88x9270xc2x0 C. and xe2x88x9230xc2x0 C., and
(b) adding about one or more equivalents of F3CCOOCH2CH3, while maintaining the temperature between about xe2x88x9270xc2x0 C. and xe2x88x9230xc2x0 C. to form a compound of formula (II-a): 
step (2) (addition)
(a) contacting about one equivalent of 5-chloro-1-pentyne with about two equivalents of n-butyllithium in a suitable aprotic solvent while maintaining a temperature of between xe2x88x9215xc2x0 C. and 20xc2x0 C. to generate cyclopropylethynyl-lithium in situ; and
(b) contacting about two or more equivalents of said cyclopropylethynyl-lithium with about one equivalent of the compound of formula (II-a) in a suitable solvent at a temperature of between xe2x88x9270xc2x0 C. and xe2x88x9210xc2x0 C. to form a compound of formula (III-a): 
step (3) (cyclization)
contacting the compound of formula (III-a) with about one or more equivalents of n-butyllithium in a suitable aprotic solvent at a temperature of between xe2x88x9270 and 0xc2x0 C. and heating to a temperature sufficient to effect intramolecular cyclization to form a compound of formula (IV-a).
In the process of the present invention, the intermediates of formula (II) and (III), may optionally be carried through to the next step without isolation of the intermediate, for example, by crystallization or chromatography, between steps in the process.
In a second embodiment, the present invention provides a novel process for the preparation of compounds of formula (IV): 
wherein
X is halogen,
R2 is trihalomethyl or pentahaloethyl,
R3 is cyclopropylethynyl; said process comprising:
(a) contacting 5-halo-1-pentyne with about two equivalents of suitable metallating agent in a suitable solvent at a temperature sufficient to generate cyclopropylethynyl-M, wherein M is lithium or magnesium halide, in situ; and
(b) contacting said cyclopropylethynyl-M with a compound of formula (II): 
xe2x80x83wherein R1 is an amine protecting group, which forms a carbamate with the amine, in a suitable solvent at a suitable temperature, and
(c) heating to a temperature sufficient to form a compound of formula (IV).
In a third embodiment, the present invention provides a process for the preparation of compounds of formula (III): 
wherein
X is halogen,
R1 is an amine protecting group, which forms a carbamate with the amine,
R2 is trihalomethyl or pentahaloethyl, and
R3 is cyclopropylethynyl; said process comprising:
(a) contacting a compound of formula (I): 
xe2x80x83with a suitable lithiating agent in a suitable aprotic solvent at a suitable temperature; and
(b) contacting the resulting product with a suitable disubstituted ketone of the formula R2COR3, to form a compound of formula (III).
In a fourth embodiment, the present invention provides a process for the preparation of compounds of formula (IV): 
wherein
X is halogen,
R2 is trihalomethyl or pentahaloethyl,
R3 is cyclopropylethynyl; said process comprising:
(a) contacting a compound of formula (I): 
xe2x80x83wherein R1 is an amine protecting group, which forms a carbamate with the amine,
xe2x80x83with a suitable lithiating agent in a suitable solvent at a suitable temperature;
(b) contacting the resultant product with a suitable disubstituted ketone of the formula R2COR3, to form a compound of formula (III); and 
(c) heating the compound of formula (III) to a temperature suitable to effect intramolecular cyclization to form a compound of formula (IV).
In a fifth embodiment, the present invention provides a process for resolving the racemate of a compound of formula (IV) to produce a stereoisomer of formula (VI): 
wherein:
X is halogen,
R2 is trihalomethyl or pentahaloethyl,
R3 is cyclopropylethynyl; said process comprising:
step (1) contacting a compound of formula (IV): 
xe2x80x83with (xe2x88x92)-camphanic acid chloride at a suitable temperature with a suitable base to form a compound of formula (V): 
xe2x80x83wherein R4 is the chiral amine protecting group camphanyl,
step (2) separating the compound of formula (V) from the resulting stereoisomers; and
step (3) removing the chiral amine protecting group by heating the compound of step (2) in a solution of DMSO and water at a sufficient temperature to effect formation of a compound of formula (VI).
In a sixth embodiment, the present invention provides a novel compound of the formula (II-a): 
In a seventh embodiment, the present invention provides a novel compound of the formula (III-a): 
In an eight embodiment, the present invention provides a novel compound of the formula (XV): 
In an ninth embodiment, the present invention provides a novel compound of the formula (XVI): 
The processes of the present invention are useful for the preparation of benzoxazinones, and compounds which are useful intermediates in the synthesis of benzoxazinones, which are useful as human immunodeficiency virus (HIV) reverse transcriptase inhibitors. Such HIV reverse transcriptase inhibitors are useful for the inhibition of HIV and the treatment of HIV infection. Such HIV reverse transcriptase inhibitors are useful for the inhibition on HIV in an ex vivo sample containing HIV or expected to be exposed to HIV. Thus, such HIV reverse transcriptase inhibitors may be used to inhibit HIV present in a body fluid sample (for example, a body fluid or semen sample) which contains or is suspected to contain or be exposed to HIV. Such HIV reverse transcriptase inhibitors are also useful as standard or reference compounds for use in tests or assays for determining the ability of an agent to inhibit viral replication and/or HIV reverse transcriptase, for example in a pharmaceutical research program. Thus, such HIV reverse transcriptase inhibitors may be used as a control or reference compound in such assays and as a quality control standard.
The following terms and abbreviations are used herein and defined as follows. The abbreviation xe2x80x9cTHFxe2x80x9d as used herein means tetrahydrofuran. The abbreviation xe2x80x9cDMSOxe2x80x9d as used herein means dimethylsulfoxide. The abbreviation or xe2x80x9cDMACxe2x80x9d as used herein means dimethylacetamide. The abbreviation xe2x80x9ctBOCxe2x80x9d or xe2x80x9cBOCxe2x80x9d as used herein means t-butyloxycarbonyl. The abbreviation xe2x80x9cBuLixe2x80x9d as used herein means butyllithium. The abbreviation xe2x80x9cNaHxe2x80x9d as used herein means sodium hydride. The abbreviation or xe2x80x9cKHMDSxe2x80x9d as used herein means potassium hexamethyldisilazide.
The reactions of the synthetic methods claimed herein are carried out in suitable solvents which may be readily selected by one of skill in the art of organic synthesis, said suitable solvents generally being any solvent which is substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which may range from the solvent""s freezing temperature to the solvent""s boiling temperature. A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step may be selected.
Suitable halogenated solvents include chlorobenzene or fluorobenzene.
Suitable ether solvents include: tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, or t-butyl methyl ether.
Suitable protic solvents may include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.
Suitable aprotic solvents may include, by way of example and without limitation, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.
Suitable basic solvents include: 2-, 3-, or 4-picoline, pyrrole, pyrrolidine, morpholine, pyridine, or piperidine.
Suitable hydrocarbon solvents include: benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.
As used herein, the term xe2x80x9camine protecting groupxe2x80x9d (or xe2x80x9cN-protectedxe2x80x9d) refers to any group known in the art of organic synthesis for the protection of amine groups which may be reacted with an amine to provide an amine protected by formation of a carbamate. Such amine protecting groups include those listed in Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d John Wiley and Sons, New York (1991), the disclosure of which is hereby incorporated by reference. Examples of amine protecting groups include, but are not limited to, the following: 1) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 2) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; and 3) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl.
Additional amine protecting groups, which form a carbamate with the amine, may include, but are not limited to, the following: 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothio-xanthyl)]methyloxycarbonyl; 2-trimethylsilylethyloxycarbonyl; 2-phenylethyloxycarbonyl; 1,1-dimethyl-2,2-dibromoethyloxycarbonyl; 1-methyl-1-(4-biphenylyl)ethyloxycarbonyl; benzyloxycarbonyl; p-nitro-benzyloxycarbonyl; 2-(p-toluenesulfonyl)ethyl-oxycarbonyl; m-chloro-p-acyloxybenzyloxycarbonyl; 5-benzyisoxazolyl-methyloxycarbonyl; p-(dihydroxyboryl)benzyloxycarbonyl; m-nitrophenyloxycarbonyl; o-nitrobenzyloxycarbonyl; 3,5-dimethoxybenzyloxycarbonyl; 3,4-dimethoxy-6-nitrobenzyloxycarbonyl; Nxe2x80x2-p-toluenesulfonylaminocarbonyl; t-amyl-oxycarbonyl; p-decyloxybenzyloxycarbonyl; diisopropylmethyloxycarbonyl; 2,2-dimethoxycarbonylvinyloxycarbonyl; di(2-pyridyl)methyloxycarbonyl; and 2-furanylmethyloxycarbonyl.
As used herein, the term xe2x80x9cchiral amine protecting groupxe2x80x9d (or xe2x80x9cchiral N-protectedxe2x80x9d) refers to any group known in the art of organic synthesis for the protection of amine groups which may be reacted with an amine to provide an amine protected with a chiral amine protecting group. Such chiral amine protecting groups include those listed in Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d John Wiley and Sons, New York (1991), the disclosure of which is hereby incorporated by reference. Examples of chiral amine protecting groups include, but are not limited to, the following: camphanyl, menthyl and borneol.
As used herein, the term xe2x80x9clithiating agentxe2x80x9d means any organometallic reagent that can deprotonate the ortho position of compound (I) to yield by substitution with an R2-substituted ester a compound of formula (II). Preferred lithiating agents are, but without limitation, alkyllithium agents. Exemplary lithiating agents include, by way of example but without limitation: n-hexyllithium, n-octyllithium, n-butyllithium, t-butyllithium, sec-butyllithium, and isobutyllithium.
As used herein, the term xe2x80x9cmetallating agentxe2x80x9d means any organometallic reagent that can effect the formation of a compound of the formula R3-M, wherein M is lithium or magnesium halide and add a R3-substituent to the carbonyl of compound (II) to yield a compound of formula (III). Preferred metallating agents are, but without limitation, lithium hydride, alkyllithium agents and Grignard reagents such as alkylmagnesium halides and arylmagnesium halides. Exemplary metallating agents include, by way of example but without limitation: n-butyllithium, sec-butyllithium, t-butyllithium, ethylmagnesium bromide, and phenylmagnesium bromide.
As used herein, the term xe2x80x9cstrong basexe2x80x9d means any organometallic reagent, metal hydride or metal alkoxide that can effect by intramolecular cyclization the formation of compound (IV) from a compound of formula (III). Preferred strong bases are, but without limitation, potassium hexamethyldisilazide, sodium hydride, potassium hydride, lithium hydride, potassium t-butoxide, phenyllithium, triphenylmethyllithium, and alkyllithium agents. Exemplary alkyllithium agents include, by way of example but without limitation: n-butyllithium, sec-butyllithium, and t-butyllithium.
As used herein, the term xe2x80x9cleaving groupxe2x80x9d (or xe2x80x94OR5) refers to any group known in the art of organic synthesis which cleaves from a substrate ester upon addition of the ester carbonyl group to another nucleophile. Such leaving groups, wherein R5 is an alkyl or a carbocyclic group, can include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, phenoxy, and benzyloxy.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro and bromo.
xe2x80x9cAlkylxe2x80x9d as used herein is intended to include both branched and straight chain saturated aliphatic hyrdocarbon groups having one to twelve carbon atoms. xe2x80x9cCarbocyclicxe2x80x9d or xe2x80x9ccarbocyclexe2x80x9d as used herein is intended to include any stable 3- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
The compounds herein described may have asymmetric centers. All chiral, diastereomeric, and racemic forms are included in the present invention. It will be appreciated that certain compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.
The present invention is contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.
The methods of the present invention, by way of example and without limitation, may be further understood by reference to Scheme 1. Scheme 1 details the general synthetic method for preparation of compounds of formula (IV). 
It is the object of the present invention to provide an improved process for the preparation of benzoxazinones which are useful as HIV reverse transcriptase inhibitors.
Step 1: Substitution: Preparation of Compound of Formula (II)
This step is conducted by reacting a compound of formula (I) in a suitable solvent at a suitable temperature with at least about two molar equivalents of a lithiating agent for a suitable length of time, followed by treatment of the activated lithiated intermediate with preferably at least about one molar equivalent, more preferably about two molar equivalents, of an ester of formula R2COOR5, to form a compound of formula (II). By way of general guidance, compound (I) in an aprotic solvent at a temperature below xe2x88x9230xc2x0 C. may be contacted with 2-3 molar equivalents of a lithiating agent for 1-2 hours followed by treatment in situ of the resulting activated lithiated intermediate with 1-3 molar equivalents of an R2COOR5 ester at a temperature below xe2x88x9230xc2x0 C. for 0.1-2 hours to form compound (II). Compound (II) may be separated from the reaction as a stable solid by quenching with a suitable agent, preferably t-butyl methyl ether, followed by standard methods of work up. An example of standard work up is shown in Example 1. Optionally, compound (II) may be carried forward in synthesis of compounds of formula (III) and (IV).
R1 is an amine protecting group, which forms a carbamate with the amine, and is preferably tert-butyloxycarbonyl or ethoxycarbonyl.
Preferred lithiating agents for step (1) include n-butyllithium, sec-butyllithium, t-butyllithium, n-hexyllithium and iso-butyllithium. A more preferred lithiating agent is sec-butyllithium.
Preferred solvents and mixtures thereof for step (1) are tetrahydrofuran and cyclohexane.
A preferred reaction time for step (1) following addition of the lithiating agent is about one hour and following addition of the ester is about 30 minutes.
A preferred temperature range for step (1) is about xe2x88x9235 to xe2x88x9245xc2x0 C.
Step 2: Addition: Preparation of Compound of Formula (III)
This step comprises the alkylation of the ketone carbonyl of a compound of formula (II) in a suitable solvent with preferably at least about one equivalent of a cyclopropylethynyl lithium, said cyclopropylethynyl lithium being generated in situ for the addition of an R3 substituent to compound (II), for a suitable length of time at a temperature sufficient to form a compound of formula (III). Generation of about three equivalents of cyclopropylethynyl lithium in situ may be carried out by contacting about three equivalents of 5-halo-1-pentyne with about six equivalents of a suitable metallating agent in a suitable solvent at a temperature below 10xc2x0 C. for 1-3 hours. Upon sufficient formation of cyclopropylethynyl lithium, about one equivalent of compound of formula (II) in a suitable solvent is added and maintained at a temperature below xe2x88x9230xc2x0 C. for 1-3 hours to form compound (III). Compound (III) may be separated from the reaction as a stable solid by standard methods of work up. An example of standard work up is shown in Example 2. Optionally, compound (III) may be carried forward in synthesis of compounds of formula (IV).
Preferred 5-halo-1-pentynes for step (2) include 5-bromo-1-pentyne and 5-chloro-l-pentyne.
Preferred metallating agents for step (2) include n-butyllithium, sec-butyllithium, t-butyllithium, iso-butyllithium, n-hexyllithium and octyllithium. A more preferred metallating agent is n-butyllithium.
Preferred solvents and mixtures thereof for step (2) are tetrahydrofuran, hexane and methyl t-butylether.
Preferred reaction times in step (2) are about two hours for generation of cyclopropylethynyl lithium and about 1.5-2 hours for addition of cyclopropylethynyl lithium to compound (II).
Preferred temperature ranges for step (2) are about xe2x88x925 to 5xc2x0 C. for generation of cyclopropylethynyl lithium and about xe2x88x9270 to xe2x88x9210xc2x0 C. for addition of cyclopropylethynyl lithium to compound (II).
Step 3: Cyclization: Preparation of Compound of Formula (IV)
This step comprises reacting a carbinol compound of formula (III) in a suitable solvent with preferably at least about one equivalent of a suitable strong base at a sufficient temperature for a suitable length of time to form a compound of formula (IV). By way of general guidance, compound (III) in an aprotic solvent at a temperature below 20xc2x0 C. may be contacted with about one molar equivalent of a strong base and heated to a temperature for 2-6 hours sufficient to form compound (IV). Compound (IV) may be separated from the reaction as a stable solid by quenching with a suitable aqueous acid, followed by standard methods of work up. An example of standard work up is shown in Example 3.
Preferred strong bases for step (3) include n-butyllithium, sec-butyllithium, t-butyllithium, n-hexyllithium, and sodium hydride. A more preferred strong base is n-butyllithium.
Preferred solvents and mixtures thereof for step (3) are toluene, hexane and tetrahydrofuran.
Reaction times for step (3) depend on the solvent and temperature. A preferred reaction time for step (3) when the solvent is toluene following addition of the strong base is about four hours.
A preferred temperature range for the addition of strong base to compound (III) in step (3) is about 0-40xc2x0 C.
Step 4: Nitrogen Protection: Preparation of Compound of Formula (V)
This step comprises the reaction of a racemic benzoxazinone compound of formula (IV) in a suitable solvent with a chiral amine protecting group. By way of general guidance, compound (IV) in an aprotic solvent may be contacted in alternating multiple additions with a total of about three equivalents of a suitable base, preferably sodium hydride or KHMDS, and a total of about 1.5 equivalents of a chiral amine protecting group at a sufficient temperature for a suitable length of time to form a compound of formula (V). Compound (V) may be separated from the reaction as a stable solid by quenching with a suitable aqueous acid, preferably acetic acid, followed by chromatography and standard methods of work up. An example of standard work up is shown in Example 4.
Preferred R4 chiral amine protecting groups for step (4) include camphanyl, menthyl and borneol. Most preferably the chiral amine protecting group is camphanyl.
Preferred solvent for step (4) is tetrahydrofuran.
Preferred reaction time for step (4) is about eight hours.
A preferred temperature range for the addition of base and chiral amine protecting group to compound (IV) in step (4) is about 0-30xc2x0 C.
Step 5: Nitrogen Deprotection: Preparation of Compound of Formula (VI)
This step comprises deprotection of the chiral amine protecting group, R4, on an isomericaly pure benzoxazinone compound of formula (V) in a suitable solvent by heating to sufficient temperature for a sufficient length of time to form a compound of formula (VI). Compound (VI) may be separated from the reaction as a stable solid by standard methods of work up. An example of standard work up is shown in Example 5.
Preferred solvents in step (4) are the mixtures of DMSO/H2O or DMAC/H2O in the ratio of 4/1. Most preferably the solvent mixture is DMSO/H2O.
Preferred reaction time for step (4) is about six hours.
Preferred temperature range in step (4) is about 100-110xc2x0 C.
The present invention may be further exemplified by, without being limited to, reference to Scheme 2.
With a judicious selection of reagents, as is well appreciated to one skilled in the art of organic synthesis, the claimed process can be performed in a straightforward manner to yield the compounds of formulas (II), (III), (IV), (V) and (VI). 
The methods of the present invention, by way of example and without limitation, may be further understood by reference to Scheme 3. This scheme details further embodiments of the general synthetic method for preparation of compounds of formula (IV) utilizing carbamate and carbinol substituents to accomplish benzoxazinone formation by intramolecular cyclization. 
Each of the references cited herein are hereby incorporated herein by reference.